JPH05339228A - 3,5-substituted benzoyl guanidine, its preparation, its use as pharmaceutic or diagnostic drug, and pharmaceutic containing that - Google Patents

Abstract

There are described benzoylguanidines of the formula I <IMAGE> where R(1) is equal to R(4)-SOm or R(5)R(6)N-SO2-, where R(4) and R(5) are equal to alk(en)yl, -CnH2n-R(7), and where R(7) is equal to cycloalkyl or phenyl, where R(5) also denotes H, R(6) is equal to H or C1-C4-alkyl, R(2) is hydrogen, halogen, alkyl, -O-(CH2)mCpF2p+1, -X-R(10), where X is equal to O, S, NR(11), R(10) is equal to H, (cyclo)alkyl(methyl), -CnH2n-R(12) where R(12) is equal to phenyl, R(3), inter alia, is defined as R(1), and their pharmaceutically tolerable salts. The compounds I are prepared by reaction of compounds of the formula II <IMAGE> in which L represents a leaving group which can be easily substituted nucleophilically, with guanidine. Compounds I are outstandingly suitable as antiarrhythmic medicaments having a cardioprotective component for infarct prophylaxis and infract treatment and for the treatment of angina pectoris, where they also preventively inhibit or strongly decrease the pathophysiological processes during the formation of ischaemically induced damage. They are moreover distinguished by a strong inhibitory action on cell proliferation. They can therefore be used as antiatherosclerotics, agents against diabetic late complications, cancers, fibrotic disorders such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidneys. They are effective inhibitors of the cellular sodium/protons antiporter (Na<+>/H<+> exchanger).

Description

Detailed Description of the Invention

The invention relates to formula I

[Chemical 3][Wherein R (1) is R (4) -SO_mOr R (5) R (6) N
-SO₂−, Where m is 0, 1 or 2,
R (4) and R (5) are C₁~ C₈-Alkyl, C₃~ C₆−
Alkenyl or -C _nH_2n-R (7) {where n is 0,
1, 2, 3 or 4 and R (7) is C_Five~ C₇-Cyclo
Alkyl, unsubstituted or
F, Cl, CF₃, Methyl, methoxy and NR (8) R
(9) (where R (8) and R (9) are H or C₁~ C_Four−
1 is a substituent selected from the group consisting of
Is phenyl substituted by 3},
R (5) also has the meaning of H, R (6) is H or C₁~
C_Four-Alkyl, or

R (5) and R (6) together can be 4 or 5 methylene groups, one of which CH ₂ groups is O, S, NH, N—CH ₃ or N. -Benzyl can be replaced by R (2) being hydrogen, F,
_{Cl, Br, C 1 ~C 4} - _{alkyl, O- (CH 2) m C} p F
_{2p + 1} or -X-R (10), wherein m is 0 or 1, p is 1, 2 or 3, X is O, S or NR (11), R (10 ) Is H, C ₁ -C ₆ -alkyl, C ₅ -C ₇ -cycloalkyl, cyclohexylmethyl, cyclopentylmethyl or —C _n H _2n —R (12)
{Where n is 0, 1, 2, 3 or 4 and R
(12) is unsubstituted or F, Cl, CF ₃ ,
Methyl, methoxy and NR (8) R (9) (where R (8)
And R (9) is H or phenyl substituted with 1 to 3 substituents selected from the group consisting of H or C ₁ -C ₄ -alkyl), and R (11) is H or C ₁ ~
C ₃ alkyl, or R (10) and R (11) may together be 4 or 5 methylene groups, one of which CH ₂ groups is O, S, NH, N--. C
Can be replaced by H ₃ or N-benzyl,

R (3) has the same definition as R (1) or is C ₁ -C ₆ -alkyl, nitro, cyano, trifluoromethyl, F, Cl, Br, I or --X--R (10). ), Where X is O, S or NR (11), R
(10) is H, C ₁ -C ₆ -alkyl, C ₅ -C ₇ -cycloalkyl, cyclohexylmethyl, cyclopentylmethyl or —C _n H _2n —R (12) {where n is 0-4 and R (12) is unsubstituted or F, Cl,
Substituent 1 selected from the group consisting of CF ₃ , methyl, methoxy and NR (8) R (9), where R (8) and R (9) are H or C ₁ -C ₄ -alkyl. ~ 3 substituted phenyl}, R (11) is H or C ₁ -C ₃ -alkyl, R (10) and R (11)
Can also together be 4 or 5 methylene groups and one CH ₂ group can be O, S, NH, N—CH ₃
Or it can be replaced by N-benzyl]
Benzoylguanidine represented by and a pharmaceutically acceptable salt thereof (however, at the same time,

R (1) is R (4) -SO _m (where m = 0 to
2) or R (5) R (6) NSO ₂ —, R (2) is halogen, C ₁ -C ₄ -alkyl and R (3) is —N
Compounds that are R (10) R (11) are excluded].

Preferred compounds of formula I are those in which R (1) is R
(4) -SO _m or R (5) R (6) N-SO _2- , where m is 0, 1 or 2, R (4) is methyl or C _n H _2n -R (7 ) {Where n is 0 or 1 and R
(7) is a substituent group 1 which is unsubstituted or is selected from the group consisting of Cl, CF ₃ , methyl and methoxy.
Is phenyl substituted by 3},
R (5) is H, C ₁ -C ₆ -alkyl, allyl or —C _n
H _2n -R (7) {where n is 0, 1, 2 or 3,
R (7) is unsubstituted or is F, Cl, CF ₃ ,
Methyl, methoxy and NR (8) R (9) (where R (8)
And R (9) is H or methyl) is phenyl substituted by 1 to 3 substituents selected from the group consisting of: and R (6) is H or methyl;
R (5) and R (6) together may be 4 or 5 methylene groups, one of which CH ₂ group is replaced by O, S, N-CH ₃ or N-benzyl. Can

R (2) is hydrogen, O--CH ₂ CF ₃ or --X
-R (10) where X is O, S or NR (11)
And R (10) is H, C ₁ -C ₆ -alkyl or —C
_n H _2n -R (12) {where n is 0 in the case of X having the meaning of oxygen or sulfur, and n is 0 or 1 in the case of X having the meaning of NR (11), and R (1
2) is phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ and methyl) and R (11) is hydrogen or C _1- C ₃ -alkyl, R (10) and R (11) can also together be 4 or 5 methylene groups, one CH ₂ group being O, S, N—CH ₃
Or it can be replaced by N-benzyl, R
(3) is methyl, nitro, cyano, trifluoromethyl,
F, Cl or -X-R (10), wherein X is O,
S or NR (11), R (10) is H, C ₁ -C ₆ −
Alkyl or _{-C n H 2n -R (12)} {n , where is 0 or 1, R (12) is or unsubstituted or substituted C
1, CF ₃ , phenyl substituted with 1 to 3 substituents selected from the group consisting of methyl and methoxy), R (11) is hydrogen or C ₁ -C ₃ -alkyl, R (10) and R (11) are also together 4
Or compounds and their pharmaceutically acceptable salts, which can also be 5 methylene groups.

Particularly preferred compounds of formula I are those in which R (1)
There R (4) -SO ₂ - or R (5) R (6) N-SO 2 - and is, where R (4) is methyl, R (5) and R (6)
Is hydrogen, an R (2) is hydrogen, -O-CH ₂ -CF ₃ or X-R (10), where X is oxygen or N-R
(11) and R (10) is H, C ₁ -C ₆ -alkyl or —C _n H _2n —R (12) (where n = 0 or 1, R (1
2) is phenyl which is unsubstituted or substituted by one of the substituents selected from the group consisting of F, Cl and methyl), and R (11) is hydrogen or C ₁ -C _3-. Alkyl and compounds wherein R (3) is methyl, F or Cl, and pharmaceutically acceptable salts thereof.

A very particularly preferred compound is 3-chloro-
4-N, N-diethylamino-5-methylsulfonylbenzoylguanidine hydrochloride and 3,4-dimethyl-5
-Sulfamoylbenzoylguanidine hydrochloride.

When one of the substituents R (1) to R (12) has an asymmetric center, the invention includes compounds having both the S and R configurations. The compounds can exist as optical isomers, diastereomers, racemates or mixtures thereof.

The intended alkyl groups can be present in either straight or branched form.

PROCESS FOR PRODUCTION The present invention further provides compounds of formula I
(= Compound I) It has formula II

[Chemical 4] Consisting of reacting a compound of the formula (wherein R (1) to R (3) have the above definitions and L is a leaving group which can be easily nucleophilically substituted) with guanidine.

Activated acid derivatives in which in formula II L is an alkoxy group, preferably a methoxy group, a phenoxy group or a phenylthio, methylthio or 2-pyridylthio group or a nitrogen heterocycle, preferably 1-imidazolyl, are the carbonyl groups which form the basis. Chloride (Formula II, L = Cl)
Is obtained in a manner known per se, for example using thionyl chloride. The carbonyl chloride itself is the carboxylic acid on which it is based (formula II, L =
OH) can be produced successively in a manner known per se.

In addition to the carbonyl chloride of formula II (L = Cl), other activated acid derivatives of formula II are also directly derived from the underlying benzoic acid derivative (formula II, L = OH). , Can be manufactured by a method known per se. For example, a methyl ester of formula II where L = OCH ₃ is treated with gaseous HCl in methanol to give an imidazolide of formula II (L = 1-imidazolyl, Staab, Angew. C
hem. Int. Ed. Engl. 1, 351-367 (196)
2)) is prepared by treatment with carbonyldiimidazole, mixed anhydride II is prepared by using Cl-COOC ₂ H ₅ or tosyl chloride in the presence of triethylamine in an inert solvent and also activation of benzoic acid. Is dicyclohexylcarbodiimide (DCC) or O-
[(Cyano (ethoxycarbonyl) methylene) amino]
-1,1,3,3-Tetramethyl-uronium tetrafluoroborate ("TOTU") (Weiss and Krommer, C
hemiker Zeitung 98,817 (1974)). A number of methods suitable for preparing the active carboxylic acid derivatives of formula II are described in the detailed section of the source literature in J. March, A.
dvanced Organic Chemistry, Third Edition (John Wi
ley & Sons, 1985), p. Shown in 350.

The reaction of the active carboxylic acid derivative of formula II with guanidine is carried out in a manner known per se in a protic or aprotic polar inert organic solvent. Methanol or THF has been found to be suitable for the reaction of methylbenzoate (II, L = OMe) with guanidine at 20 ° to the boiling point of the solvent. For the majority of the reaction of compound II with salt-free guanidine it was advantageous to carry out the reaction in an aprotic inert solvent such as THF, dimethoxyethane or dioxane. However, in the above reaction of II with guanidine, a base such as Na
If OH is used, water can also be used as solvent.

When L = Cl, the reaction is advantageously carried out with the addition of an acid scavenger in the form of excess guanidine which binds hydrohalic acid, for example.

Some of the basic benzoic acid derivatives of formula II are known and described in the literature. The unknown compounds of formula II can be prepared by methods known in the literature.

Formula II (eg L = -OH) wherein R (2) has the meaning of halogen or R (3) has the meaning of nitro.
Or -O-methyl) carboxylic acids or their esters can be used on the other side as starting compounds for other carboxylic acids of the formula II. The halogen at the R (2) position can be replaced by a number of nucleophiles such as mercaptan R
(10) -SH, phenol R (10) -OH or primary or secondary amines R (10) R (11) NH with very convenient displacement in a known manner L = -OH or-
It is possible to produce other benzoic acid derivatives II which are O-methyl or to convert the nitro to a number of reactions after reductive conversion to NH ₂ (alkylation, acylation or diazotization, followed by sanding. Can be converted to other benzoic acid derivative II in which L = -OH or -O-methyl by Meyer, Ullmann, Meyerwine, etc. reactions.

In general, benzoylguanidine I is a weak base and can combine with acids to form salts. Possible acid addition salts are all pharmaceutically acceptable acid salts, such as halides, especially hydrochlorides, lactates, sulphates, citrates, tartrates, acetates, phosphates, methanesulphonates and p-toluenesulfonate.

Compound I is a substituted acylguanidine.
The main ester representing acylguanidine is the pyrazine derivative amiloride, which has been used therapeutically as a potassium-sparing diuretic. Numerous other compounds of the amiloride type have been described in the literature, for example dimethyl amiloride or ethyl isopropyl amiloride.

[0020]

[Chemical 5]

Further studies have been disclosed showing the antiarrhythmic properties of amiloride (Circulation 79, 1257).
-63 (1989)). However, the only obstacle to its widespread use as an antiarrhythmic agent is that this effect is of minimal significance and is associated with antihypertensive and salt excretory effects and these side effects are associated with the treatment of cardiac arrhythmias. The point is that it is not desirable.

The indication of the antiarrhythmic properties of amiloride was also made in experiments on isolated animal hearts (Eur. Heart).
J. 9 (suppl. 1): 167 (1988) (abstract book)). For example, it was found that artificially generated ventricular fibrillation can be completely suppressed by amiloride in rat heart. The amiloride derivative ethyl isopropyl amiloride was even more potent than amiloride in this model.

US Pat. No. 5,091,394 (HOE
89 / F 288) describes benzoylguanidines bearing a hydrogen atom at the position corresponding to the group R (3).

US Pat. No. 3,780,027 claims acylguanidines derived from commercially available loop diuretics such as bumetanide, which are structurally similar to compounds of formula I. .. Strong salt diuretic (salidiureti)
c) The activity is correspondingly reported for these compounds.

It was therefore surprising that the compounds according to the invention do not possess the undesired adverse diuretic properties but possess the very good antiarrhythmic properties exerted, for example, in the case of hypoxia. As a result of their pharmacological properties, the compounds are very suitable as antiarrhythmic preparations with cardioprotective components for infarction prevention and treatment and angina treatment. They also preventively prevent or greatly reduce the pathophysiological processes in the development of ischemia-induced injury, in particular ischemia-induced cardiac arrhythmias. Due to their protective action against pathological hypoxia and ischemic conditions, the compounds of the invention of the formula I are the result of the inhibition of the cellular Na ⁺ / H ⁺ exchange mechanism, resulting in ischemia or the primary or It can be used as a therapeutic formulation for all acute or chronic injuries caused by secondary diseases. This relates to their use as formulations in the involvement of surgical procedures such as organ transplants. There, the compounds of the present invention may be applied to protect the donor's organs and excised organs before or during depletion, for example during treatment or storage thereof in physiological baths and during transplantation into the recipient's body. It can be used in both cases. The compounds are also useful protective formulations during the treatment of cardiovascular and peripheral vascular angioplastic surgery involvement, for example. Due to their protective effect against ischemia-induced damage, the compounds are also suitable as formulations for the treatment of ischemia of the nervous system, in particular the central nervous system. For example, they are suitable for the treatment of stroke or hydrocephalus. Furthermore,
The compounds of the invention of the formula I are suitable for the treatment of shock forms such as allergic, cardiogenic, hypovolemia and bacterial shock.

Furthermore, the compounds of the invention of the formula I are characterized by having a potent inhibitory effect on cell proliferation, for example fibroblast proliferation and vascular smooth muscle cell proliferation. That is, the compounds of formula I can be considered as useful therapeutic agents for diseases in which cell proliferation is the primary or secondary cause. Thus, the compounds are useful as anti-atherosclerotic agents as well as late-onset diabetic complications, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or renal fibrosis, organ hypertrophy and hyperplasia, especially prostatic hyperplasia or It can be used as an agent for prostatic hypertrophy.

The compounds of the present invention are inhibitors of the activity of the cellular sodium-proton alternation transport mechanism (Na ⁺ / H ⁺ exchanger). This alternation mechanism occurs in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) in easily measurable cells such as red blood cells, platelets or white blood cells. Therefore, the compound of the present invention is an excellent and simple scientific tool for use as a diagnostic agent for measuring and differentiating, for example, certain forms of hypertension and also atherosclerosis or diabetes, proliferative diseases and the like. Is suitable as Furthermore, the compounds of formula I are also suitable for prophylactic treatment to prevent hypertension, eg essential hypertension.

Formulation Preparation Formulations containing Compound I may be administered orally, parenterally, intravenously, rectally or by inhalation, with the preferred administration depending on the particular type of disease. Compound I
Can be used on its own or with formulation aids to be compatible with veterinary or human medicine.

The auxiliaries suitable for the desired formulation are familiar to the person skilled in the art. In addition to solvents, gelling agents, suppository bases, tabletting aids and other active compounds, for example excipients, antioxidants, dispersants, emulsifiers, defoamers, flavor modifiers, preservatives, solubilizers. Agents or colorants can be used.

In oral dosage forms, the active compound is mixed with orally suitable additives such as excipients, solubilizers or inert diluents, and then in a conventional manner suitable dosage forms such as tablets, coated tablets, hard gelatine. Capsules or aqueous, alcoholic or oily solutions. Examples of inert excipients that can be used include gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose,
There is glucose or starch, especially corn starch.
The preparation here can be carried out as both dry and wet granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compound is
If desired, the substances which are customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, are brought into solution, suspension or emulsion. Suitable solvents are, for example, water, saline or alcohols such as ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions or also mixtures of the various solvents mentioned.

Formulations suitable for administration in aerosol or spray form are, for example, solutions, suspensions or emulsions of the active compound of formula I in a pharmaceutically acceptable solvent, especially ethanol or water or a mixture of these solvents. Is. If desired, the formulation can also contain further pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and propellant gases. Such formulations usually contain the active compound in a concentration of about 0.1 to 10% by weight, in particular about 0.3 to 3% by weight.

The amount of active compound of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compound used, as well as the type and severity of the disease to be treated and the sex, age, weight and individual of the mammal to be treated. It depends on the reactivity.

On average, the daily dose of the compound of formula I for a patient of about 75 kg is at least 0.001 mg / kg of body weight, preferably 0.01-10 mg, more preferably 1 mg. Acute manifestations of the disease, for example immediately after suffering a cardiac infarction, may require higher, especially more frequent, doses, eg, up to 4 individual doses per day. In particular, up to 200 mg per day may be required for intravenous administration, for example in the case of infarct patients in the intensive care unit.

Experiment Benzoylguanidine from benzoic acid (II, L = OH)
General procedure for preparing (I) 0.01 mol of the benzoic acid derivative of the formula II is dissolved or suspended in 60 ml of anhydrous tetrahydrofuran (THF) and then 1.78 g (0.011 mol) of carbonyldiimidazole. To process. After stirring at room temperature for 2 hours, guanidine 2.9
5 g (0.05 mol) are placed in this reaction solution. After stirring overnight, THF was distilled off under reduced pressure (Rotavapor), the residue was treated with water and the mixture was adjusted to pH 6 with 2N HCl.
Adjust to ~ 7 and filter off the corresponding benzoylguanidine (Formula I). The benzoylguanidine thus obtained can be converted to the corresponding salt by treatment with aqueous or methanolic hydrochloric acid or other pharmaceutically acceptable acid.

[0036]

【Example】

 Example 1

[Chemical 6]

3-Chloro-5-methylsulfonylbenzoylguanidine hydrochloride: colorless crystals, melting point 230 ° C. Synthetic routes: a) Reduction of 3-chloro-5-chlorosulfonylbenzoic acid with sodium bisulfite in water at 10-15 ° C and constant pH 8-9 (NaOH, glass electrode) to 3-chloro-5-. Make carboxybenzenesulfinic acid, acidify with HCl and then filter off the white precipitate. b) The disodium 3-chloro-5-carboxybenzenesulfinate is obtained from a) with 2 equivalents of NaOH in water, evaporated, suspended in acetone and the crystals are filtered off. White crystals, melting point> 300 ° C. c) from b) to 8 with 1 equivalent of methyl iodide in DMF
Methyl 3-chloro-5-methylsulphonylbenzoate is obtained at 0 ° C./8 hours, the solvent is distilled off and subjected to column chromatography on silica gel with an ethyl acetate / toluene mixture (1: 3). Colorless crystals, melting point 75 ° C. d) 3-chloro-from c) by alkaline hydrolysis
5-Methylsulfonylbenzoic acid is obtained and then acidified with HCl. White crystalline powder, melting point 214 ° C. e) 3-chloro-5-methylsulfonylbenzoylguanidine hydrochloride is obtained from d) by the general procedure (see above). Colorless crystals, melting point 230 ° C.

Example 2

[Chemical 7]

3,4-Dimethyl-5-methylsulfonylbenzoylguanidine hydrochloride: colorless crystals, melting point 288
° C. Synthetic route: a) Reduction of 5-chlorosulfonyl-3,4-dimethylbenzoylbenzoic acid with sodium bisulfite to give 2,3-dimethyl-5-carboxybenzenesulfinic acid in a manner similar to Example 1, a). .. White crystals, melting point 2
13 ° C. b) The disodium 2,3-dimethyl-5-carboxybenzenesulfinate is obtained from 2,3-dimethyl-5-carboxybenzenesulfinic acid in a manner similar to Example 1, b). Colorless crystals, melting point> 320 ° C. c) Disodium 2, in a manner similar to Example 1, c)
Methyl 3,4-dimethyl-5-methylsulfonylbenzoate is obtained from 3-dimethyl-5-carboxybenzenesulfinate. Colorless crystals, melting point 102 ° C. d) 3,4 from methyl 3,4-dimethyl-5-methylsulfonylbenzoate in a manner similar to Example 1, d).
-Dimethyl-5-methylsulfonylbenzoic acid is obtained. Obtained as colorless crystals from ethanol. Melting point 224 [deg.] C. e) 3,4-Dimethyl-5-methylsulfonylbenzoylguanidine hydrochloride is obtained from 3,4-dimethyl-5-methylsulfonylbenzoic acid according to the general procedure. Colorless crystals, melting point 288 ° C.

Example 3

[Chemical 8]

3,4-dimethyl-5 according to the general procedure
-Sulfamoylbenzoic acid to 3,4-dimethyl-5-
Sulfamoylbenzoylguanidine hydrochloride is obtained. Colorless crystals, melting point 270 ° C.

[0042]

[Chemical 9]

5- (1-butylsulfamoyl) -3,
4-dichlorobenzoylguanidine hydrochloride is 3,4-
Dichlorobenzoic acid and chlorosulfonic acid 140-160
To give 3,4-dichloro-5-chlorosulfonylbenzoic acid (melting point: 203 ° C), which was reacted with N-butylamine to react with 5- (1-butylsulfamoyl) -3,4- Dichlorobenzoic acid (melting point 160-165
℃) then activated with carbonyldiimidazole to react with guanidine and treated with HCl to give 5
It is obtained by making-(1-butylsulfamoyl) -3,4-dichlorobenzoylguanidine hydrochloride.
Melting point 140-145 [deg.] C.

Example 5

[Chemical 10] 5-N-benzyl-N-methylsulfamoyl-3,4
-Dichlorobenzoylguanidine hydrochloride was prepared by reacting 3,4-dichloro-5-chlorosulfonylbenzoic acid with N-methylbenzylamine to obtain 5-N-benzyl-N-methylsulfamoyl-3,4-dichlorobenzamide ( Melting point 155-160 ° C) and then carrying out the reaction according to the general procedure (see above). Colorless crystals, melting point 185-190 ° C.

Example 6

[Chemical 11] 3,4-Dichloro-5-sulfamoylbenzoylguanidine hydrochloride (colorless crystalline substance, melting point 234-236
° C) is obtained from 3,4-dichloro-5-sulfamoylbenzoic acid according to the general procedure (see above).

Example 7

[Chemical formula 12] 3,4-Dichloro-5-methylsulfonylbenzoylguanidine hydrochloride (colorless crystals, melting point 236-240 ° C)
Starts from 3,4-dichloro-5-chlorosulfonylbenzoic acid and reduces with sulfite to give disodium 2,3-dichloro-5-carboxybenzenesulfinate (melting point> 300 ° C), which is Reaction with excess methyl iodide gave methyl 3,4-dichloro-5-methylsulfonylbenzoate, which was hydrolyzed to give 3,4
-Dichloro-5-methylsulfonylbenzoic acid (196-
199 ° C.) and then the reaction is performed according to a general method.

Example 8

[Chemical 13] 3-chloro-4-N, N-diethylamino-5-methylsulfonylbenzoylguanidine hydrochloride (colorless crystals, melting point 222-224 [deg.] C.) is methyl 3,4-dichloro-5.
Starting from methylsulfonylbenzoate, reacting with diethylamine in an autoclave (160 ° C., 12 h) and then subjected to alkaline hydrolysis to 3-chloro-4.
Obtained by obtaining -N, N-diethylamino-5-methylsulfonylbenzoic acid (mp 115-117 ° C) and carrying out the reaction with guanidine according to the general procedure (see above).

Example 9

[Chemical 14] 3-chloro-5-methylsulfonyl-4-phenoxybenzoylguanidine hydrochloride (colorless crystals, melting point 271-2)
74 ° C), starting from methyl 3,4-dichloro-5-methylsulfonylbenzoate, reacted with phenol and potassium carbonate in DMF (80 ° C, 6.5 hours) and then subjected to alkaline hydrolysis. 3-chloro-5-methylsulfonyl-4-phenoxybenzoic acid (melting point 210-
212 ° C.) and is reacted with guanidine according to the general procedure (see above).

Example 10

[Chemical 15] 3-chloro-5-methylsulfonyl-4-phenylthiobenzoylguanidine hydrochloride (colorless crystals, melting point 228-
230 ° C.) starting from methyl 3,4-dichloro-5-methylsulfonylbenzoate, reacted with thiophenol and potassium carbonate in DMF (120 ° C., 6.5 hours) and then subjected to alkaline hydrolysis to 3 -Chloro-5
-Methylsulfonyl-4-phenylthiobenzoic acid (mp 231-233 ° C) and general procedure (see above)
It is obtained by reacting with guanidine according to.

Example 11

[Chemical 16] 3-Benzylsulfonyl-4,5-dichlorobenzoylguanidine hydrochloride (colorless crystals, melting point 262 ° C.) was reacted with disodium 2,3-dichloro-5-carboxybenzene sulfonate in DMF with 2 equivalents of benzyl chloride (80 ° C., 5 hours) then acid hydrolysis (20% HCl)
5-Benzylsulfonyl-3,4-dichlorobenzoic acid (melting point 183)
C.) and then reacted with guanidine according to the general procedure.

Example 12

[Chemical 17] 4- (1-Butylamino) -3-chloro-5-methylsulfonylbenzoylguanidine dihydrochloride (colorless crystals, melting point 200 ° C) is 3,4-dichloro-5-methylsulfonylbenzoic acid (melting point 215-220 ° C). Reaction with n-butylamine in an autoclave (140 ° C.,
12 hours) and then 4- (1-butylamino) -3-chloro-5-methylsulfonylbenzoic acid (melting point 155-16
0 ° C.) which is obtained by reacting it with guanidine according to the method described above (see above).

Example 13

[Chemical 18] 4-Amino-3-chloro-5-methylsulfonylbenzoylguanidine dihydrochloride (colorless crystals, melting point 270 ° C) starts from 4-amino-3-chloro-5-methylsulfonylbenzoic acid (melting point 255-261 ° C). It is obtained by reacting with guanidine according to the above method (see above).

Example 14

[Chemical 19] 3-chloro-4- (2,2,2-trifluoroethoxy)
-5-Methylsulfonylbenzoylguanidine hydrochloride (colorless crystals, melting point 261 [deg.] C) starts from methyl 3,4-dichloro-5-methylsulfonylbenzoate
Reaction with 2,2,2-trifluoroethanol and potassium carbonate in MF (100 ° C., 6 hours) followed by alkaline hydrolysis to give 3-chloro-4- (2,2,2-trifluoroethoxy). ) -5-Methylsulfonylbenzoic acid (mp 214-220 ° C) is obtained by reacting it with guanidine according to the method described above (see above).

Example 15

[Chemical 20] 3-sulfamoyl-5-trifluoromethylbenzoylguanidine hydrochloride (colorless crystals, melting point 235-238
C) was subjected to reaction by nitration of 3-trifluoromethylbenzoic acid (20% 100% HNO _{3 in} fuming sulfuric acid, 3 hours at room temperature) to give 5-nitro-3-trifluoromethylbenzoic acid (melting point). 126-129 ° C) and then catalytic hydrogenation (platinum (IV) oxide in ethanol at room temperature, 1 atm) to give 5-amino-3-trifluoromethylbenzoic acid (melting point 133-137 ° C). , It was subjected to Meerwein reaction to give 5-chlorosulfonyl-3-
Trifluoromethylbenzoic acid (melting point 144-147 ° C)
To give 5-sulfamoyl-3-trifluoromethylbenzoic acid (mp 235-240 ° C.) by reacting with aqueous ammonia solution (25%, 14 hours at room temperature) and then reacting with guanidine according to the above method (see above). It is obtained by

Example 16

[Chemical 21] 3-Amino-5-methylsulfonylbenzoylguanidine dihydrochloride (colorless crystals, melting point 264 ° C.) nitrates 3-methylsulfonylbenzoic acid (1% in 20% fuming sulfuric acid).
5% by reaction with 00% HNO ₃ at room temperature for 3 hours)
-Nitro-3-methylsulfonylbenzoic acid (melting point 218
˜220 ° C.), then catalytic hydrogenation (Raney-Nickel in methanol, room temperature, 1 atm) to give 5-amino-3-methylsulfonylbenzoic acid (mp 300-310 ° C.),
It is then obtained by reacting with guanidine according to the method described above (see above).

Example 17

[Chemical formula 22] 3-Amino-4-chloro-5-methylsulfonylbenzoylguanidine dihydrochloride (colorless crystals, melting point 279-28
1 ° C.) nitrated 4-chloro-3-methylsulfonylbenzoic acid (100% HNO ₃ , 9 in 20% fuming sulfuric acid).
4-chloro-5-nitro-3-methylsulfonylbenzoic acid (melting point 1
90-194 ° C.), which is reduced with sodium bisulfite (1 hour, 100 ° C. in water) 5-amino-4-chloro-3-methylsulfonylbenzoic acid (mp 265-2.
67 ° C.) and then reacted with guanidine according to the method described above (see above).

Example 18

[Chemical formula 23] 3-Cyano-5-methylsulfonylbenzoylguanidine hydrochloride (colorless to slightly yellow crystals, melting point 275-27)
8 ° C. (decomposition) is carried out by sand-meier (Sa) of 3-amino-5-methylsulfonylbenzoic acid with copper (I) cyanide.
ndmeyer) reaction to give 3-cyano-5-methylsulfonylbenzoic acid (mp 226-228 ° C), which is then reacted with guanidine according to the method described above (see above).

Example 19

[Chemical formula 24] 3-chloro-4-methyl-5-sulfamoylbenzoylguanidine hydrochloride (colorless crystals, melting point 256-259
C.) is obtained from 3-chloro-4-methyl-5-sulfamoylbenzoic acid by reaction with guanidine according to the method described above (see above).

Example 20

[Chemical 25] 3-Dimethylamino-5-methylsulfonylbenzoylguanidine hydrochloride (colorless crystals, melting point 278-290 ° C)
(Decomposition) is the reaction of 3-amino-5-methylsulfonylbenzoic acid with methyl iodide in DMF / potassium carbonate (6 hours, 70 ° C.) followed by hydrolysis to 3-dimethylamino-5-methyl. Sulfonylbenzoic acid (melting point 200-
203 ° C.) and reacting it with guanidine according to the method described above (see above).

Example 21

[Chemical formula 26] 3-chloro-4- (4-chlorobenzylamino) -5-
Methylsulfonylguanidine hydrochloride was prepared according to the method described above using 3-chloro-4- (4-chlorobenzylamino) -5-
Obtained from methylsulfonylbenzoic acid and guanidine. Colorless crystals, melting point 209-219 ° C.

Example 22

[Chemical 27] 3- (2,5-Dimethoxy-4-methylphenylsulfonyl) -5-trifluoromethylbenzoylguanidine hydrochloride was prepared according to the above-mentioned method using 3- (2,5-dimethoxy-4-methylphenylsulfonyl) -5-trifluoro. Methylbenzoic acid and guanidine are obtained. Colorless crystals, melting point 174 ° C.

Example 23

[Chemical 28] 4-anilino-3-chloro-5-methylsulfonylbenzoylguanidine hydrochloride is obtained from 4-anilino-3-chloro-5-methylsulfonylbenzoic acid and guanidine according to the method described above. Colorless crystals, melting point 174 ° C.

4-anilino-3-chloro-5-methylsulfonylbenzoic acid (melting point 187-189 ° C.) was 1. Methyl 3,4-dichloro-5-methylsulfonyl benzoate was added in excess aniline at 8O <0> C for 8 hours.
Methyl 4-anilino-3-chloro-5-methylsulfonylbenzoate (mp 165-169 ° C) by heating for 10 hours and treating the reaction mixture with 1N HCl.
And then 2. Methyl 4-anilino-3-chloro-5-methylsulphonylbenzoate is hydrolyzed with methanolic / aqueous NaOH and the residue is taken up in 2N HC after evaporation of the solvent mixture.
It is obtained by treating with l.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/155 ADP ADU 31/18 ABP 8413-4C ABS ACV 31/275 ACS C07C 311/37 7419- 4H 311/39 7419-4H 323/65 7419-4H (72) Inventor Andreas Wueichert, Federal Republic of Germany Day 6000 Frankfurt am Main. Lauenter Ravwek 11 (72) Inventor Wolfgang Schjorz, Federal Republic of Germany Day-6236 Escheuborn. Unter Ortschütlerse 30 (72) Inventor Oud Arbus Day 6364 Florschutt. Am Remarkaster 9 (72) Heinrich Engrat, Federal Republic of Germany Day-6238 Hofheim am Taunus. Schuttorm Schutlerse 13 (72) Inventor Florian Lang Day 7777 Markukdorf. Leaphard 12

Claims (10)

[Claims] 1. Formula I[Wherein R (1) is R (4) -SO_mOr R (5) R (6) N-SO₂−
Where m is 0, 1 or 2 and R (4) and R (5) are C₁~ C₈-Alkyl, C₃~ C₆−
Alkenyl or -C _nH_2n-R (7) {where n is 0,
1, 2, 3 or 4 and R (7) is C_Five~ C₇-Cyclo
Alkyl, unsubstituted or
F, Cl, CF₃, Methyl, methoxy and NR (8) R
(9) (where R (8) and R (9) are H or C₁~ C_Four−
1 is a substituent selected from the group consisting of
Is phenyl substituted by 3}, R (5) also has the meaning of H, and R (6) is H or C₁~ C_Four-Alkyl or R
(5) and R (6) are 4 or 5 methyl groups together
CH groups, one of which is CH₂The basis is
O, S, NH, N-CH₃Or by N-benzyl
R (2) is hydrogen, F, Cl, Br, C₁~ C_Four-Alkyl,
O- (CH₂)_mC_pF_{2p +1}Or -X-R (10),
Where m is 0 or 1, p is 1, 2 or 3, X is O, S or NR (11), R (10) is H, C₁~ C₆-Alkyl, C_Five~ C₇-Cyclo
Alkyl, cyclohexylmethyl, cyclopentylmethyl
Le or -C_nH_2n-R (12) {where n is 0, 1,
2, 3 or 4 and R (12) is not substituted
Squid or F, Cl, CF₃, Methyl, methoxy and
NR (8) R (9) (where R (8) and R (9) are H or
C₁~ C_Four-Alkyl)
Is phenyl substituted with 1 to 3 substituents}
R (11) is H or C₁~ C₃Alkyl or R
(10) and R (11) together form 4 or 5 members.
Can be a thylene group, one of which is CH₂Basis
Is O, S, NH, N-CH₃Or by N-benzyl
R (3) has the same definition as R (1) or is C₁~ C₆
-Alkyl, nitro, cyano, trifluoromethyl,
F, Cl, Br, I or -X-R (10), where
And X is O, S or NR (11), R (10) is H, C₁~ C₆-Alkyl, C_Five~ C₇-Cyclo
Alkyl, cyclohexylmethyl, cyclopentylmethyl
Le or -C_nH_2n-R (12) {where n is 0-4
And R (12) is unsubstituted or F, C
l, CF₃, Methyl, methoxy and NR (8) R (9)
(Where R (8) and R (9) are H or C₁~ C_Four-Al
1 to 3 substituents selected from the group consisting of
Is phenyl substituted with R} and R (11) is
H or C₁~ C₃-Alkyl, R (10) and R (11) also taken together are 4 or 5
Can be one methylene group and one CH₂The basis is
O, S, NH, N-CH₃Or by N-benzyl
Can be replaced]
Gin and pharmaceutically acceptable salts thereof (provided that
And R (1) is R (4) -SO_m(Where m = 0-2) or R
(5) R (6) NSO₂-, R (2) is halogen, C₁~ C_Four-Alkyl and R
Exclude compounds where (3) is -NR (10) R (11)
]. 2. R (1) is R (4) -SO _m or R (5) R
(6) N-SO ₂ - where m is 0, 1 or 2, R (4) is methyl or _{-C n H 2n -R (7)} { wherein n is 0 or 1 , R (7) is phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of Cl, CF ₃ , methyl and methoxy} and R (5) is H, C ₁ ~C ₆ - alkyl, allyl or -C _n
H _2n -R (7) {where n is 0, 1, 2 or 3,
R (7) is unsubstituted or is F, Cl, CF ₃ ,
Methyl, methoxy and NR (8) R (9) (where R (8)
And R (9) is H or methyl) is phenyl substituted by 1 to 3 substituents selected from the group consisting of: R (6) is H or methyl, or R (5) and R
(6) taken together may be 4 or 5 methylene groups, one of which CH ₂ groups is O, S, NC
H ₃ or N-benzyl, R (2) is hydrogen, O—CH ₂ CF ₃ or —X—R (10), where X is O, S or NR (11). , R (10) is H, C ₁ -C ₆ -alkyl or —C _n H _2n —
R (12) {where n in the case of X having the meaning of oxygen or sulfur is 0 and X having the meaning of NR (11)
Where n is 0 or 1 and R (12) is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ and methyl. R (11) is hydrogen or C ₁ -C ₃ -alkyl and R (10) and R (11) are also taken together as 4 or 5
Methylene groups, one CH ₂ group can be replaced by O, S, N—CH ₃ or N-benzyl, and R (3) is methyl, nitro, cyano, trifluoromethyl, F , Cl or —X—R (10), where X is O, S or NR (11), and R (10) is H, C ₁ -C ₆ -alkyl or —C _n H _2n —.
R (12) {where n is 0 or 1 and R (12) is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Cl, CF ₃ , methyl and methoxy. Phenyl), R (11) is hydrogen or C ₁ -C ₃ -alkyl, R (10) and R (11) are also taken together as 4 or 5
The compounds of claim 1 and their pharmaceutically acceptable salts which can be methylene groups. 3. R (1) is R (4) —SO ₂ — or R (5)
_{R (6) N-SO 2} - and is, where R (4) is methyl, R (5) and R (6) is hydrogen, R (2) is hydrogen, -O-CH ₂ - CF ₃ or X-R (10)
Where X is oxygen or N—R (11) and R (10) is H, C ₁ -C ₆ -alkyl or —C _n H _2n —.
R (12), where n = 0 or 1, R (12) is phenyl which is unsubstituted or substituted by one substituent selected from the group consisting of F, Cl and methyl. Wherein R (11) is hydrogen or C ₁ -C ₃ -alkyl and R (3) is methyl, F or Cl, and pharmaceutically acceptable salts thereof. 4. A compound selected from the group consisting of 3-chloro-4-N, N-diethylamino-5-methylsulfonylbenzoylguanidine hydrochloride and 3,4-dimethyl-5-sulfamoylbenzoylguanidine hydrochloride. 1
The described compound. 5. Formula II: 3. A compound of formula (I) wherein R (1) -R (3) have the definitions given above and L is a leaving group which can be readily nucleophilically substituted and is reacted with guanidine. A method for producing the described compound. 6. Use of a compound according to claim 1 for the manufacture of a medicament for treating arrhythmia or angina. 7. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of cardiac infarction. 8. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of ischemic conditions of the heart. 9. A method according to claim 1 in the manufacture of a medicament for treating diseases in which fibroblast proliferation is the primary or secondary cause.
Use of the described compounds, ie as anti-atherosclerotic agents and as agents for late-onset diabetic complications, cancer and fibrogenic disorders such as pulmonary fibrosis, liver fibrosis or renal fibrosis. 10. Use of a compound according to claim 1 for the manufacture of a scientific tool for blocking the Na ⁺ / H ⁺ exchanger for the diagnosis of hypertension and proliferative disorders.